Interpretive Summary: In this study, a novel orally active drug-candidate was used to test the hypothesis that increasing epoxyeicosatrienoic acids by inhibition of soluble epoxide hydrolase (sEH) would lower blood pressure and ameliorate renal damage in salt-sensitive hypertension. Hypertension was produced in rats by infusing them with angiotensin for 14 days while being they were fed either a normal or high salt diet which included the sEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA). The AUDA reduced blood pressure in both groups of rats, while increasing the urine levels of epoxides relative to their sEH-dependent diol metabolites. Markers of renal damage were reduced in both high and normal salt groups, while markers of macrophage infiltration were reduced in the high salt group. These data demonstrate that sEH inhibition lowers blood pressure and ameliorates renal damage in angiotensin-dependent, salt-sensitive hypertension.

Technical Abstract:
The present study tested the hypothesis that increasing epoxyeicosatrienoic acids by inhibition of soluble epoxide hydrolase (sEH) would lower blood pressure and ameliorate renal damage in salt-sensitive hypertension. Rats were infused with angiotensin and fed a normal-salt diet or an 8% NaCl diet for 14 days. The sEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), was given orally to angiotensin-infused animals during the 14-day period. Plasma AUDA metabolite levels were measured, and they averaged 10+/-2 ng/mL in normal-salt angiotensin hypertension and 19+/-3 ng/mL in high-salt angiotensin hypertension on day 14 in the animals administered the sEH inhibitor. Mean arterial blood pressure averaged 161+/-4 mm Hg in normal-salt and 172+/-5 mm Hg in the high-salt angiotensin hypertension groups on day 14. EH inhibitor treatment significantly lowered blood pressure to 140+/-5 mm Hg in the normal-salt angiotensin hypertension group and to 151+/-6 mm Hg in the high-salt angiotensin hypertension group on day 14. The lower arterial blood pressures in the AUDA-treated groups were associated with increased urinary epoxide-to-diol ratios. Urinary microalbumin levels were measured, and ED-1 staining was used to determine renal damage and macrophage infiltration in the groups. Two weeks of AUDA treatment decreased urinary microalbumin excretion in the normal-salt and high-salt angiotensin hypertension groups and macrophage number in the high-salt angiotensin hypertension group. These data demonstrate that sEH inhibition lowers blood pressure and ameliorates renal damage in angiotensin-dependent, salt-sensitive hypertension.